On the women's side, second-seeded Maria Sharapova, who beat Eugenie Bouchard on Tuesday, and Ekaterina Makarova are still around and will play an all-Russian semifinal.
Nadal's lack of match fitness from nearly six months of injuries and illness finally caught up with the 14-time major champion in his quarterfinal match against Tomas Berdych. He was never much of a factor and lost 6-2, 6-0, 7-6 (5).
The third-seeded Nadal said before the tournament that his inactivity over the last half of 2014 made him unlikely to win more than a few rounds. Coming into the Australian Open, Nadal had played only eight matches since last June because of a right wrist injury and appendix surgery in November.
Federer, who has 17 major titles, including four in Australia, departed Melbourne Park after an upset third-round loss to Andrea Seppi.
Nadal said he was surprised to have advanced as far as he did in Melbourne.
"It is obvious that I needed something more to be more competitive," Nadal said. "As I said when I arrived here, the process always is not easy. When you have injuries, comebacks are difficult. But without being at my top level of tennis, I was able to be here in quarterfinals. Is not a bad result at all for me."
Berdych said, "I was ready for everything and I think that was the difference ... when you're playing Rafa you have to keep going to the last point."
The seventh-seeded Berdych, who had lost 17 straight matches to Nadal, will play sixth-seeded Andy Murray in the semifinals after the British player beat local hope Nick Kyrgios 6-3, 7-6 (5), 6-3 in a night match.
Kyrgios came back from two sets down and saved a match point in the fourth round Sunday before beating Italian Andreas Seppi, the player who had eliminated Federer, but there was no such comeback on Tuesday.
The 19-year-old Kyrgios, who walked onto the court with his headphones on and gave two thumbs-up to the crowd, was at his crowd-pleasing best. After hitting a backhanded drop shot at the net for winner in the second set, he spread out his arms for applause, and in the third set, he hit a between-the-legs shot that Murray easily returned.
"It was a tricky match," Murray said. "I tried to start as quick as possible because I know how dangerous Nick is. He's a huge hitter of the ball, so I tried to keep it out of his strike zone as much as possible. Thankfully it worked."
Sharapova moved closer to another Australian Open title, defeating 20-year-old Bouchard 6-3, 6-2.The Russian made all the big points look easy and advanced to play Makarova, who earlier beat third-seeded Simona Halep 6-4, 6-0.
"I felt pretty good from the start, didn't feel I had too many letdowns," Sharapova said, adding that her close call in the second round — facing two match points against a qualifier — sharpened her focus for the rest of the tournament.
The last time Sharapova and Bouchard met — in the semifinals at the French Open last year — Bouchard won the first set before Sharapova came back to take the next two. The Russian then won the title at Roland Garros.
This time, Bouchard, who made the finals of Wimbledon and two other Grand Slam semis last year, didn't come close to taking a set, looking flat from the outset while being broken in her opening service game. The Genie Army, a group of young Australian men who croon about the Canadian player, was left to sing another day.
"She didn't give me many chances, and against the great players you have to take any chances you can get," Bouchard said.
The other women's semifinalists will be determined on Wednesday when No. 1-ranked Serena Williams plays last year's finalist, Dominika Cibulkova, and Venus Williams, playing in her first Grand Slam quarterfinal in nearly five years, takes on 19-year-old American Madison Keys.
If the Williams sisters play each other in the semifinals, it would be their first meeting in a Grand Slam tournament since the Wimbledon final in 2009 — won by Serena.